Project 1 is fundamental to the overall program. In this project, we will develop a matrix of data that defines how the major nutritional and genetic factors responsible for colonic cancer interact to alter intestinal homeostasis and probability of tumor formation. We will use three mouse genetic models: two already established and well characterized by us - the Apc1638 and the Muc2 mouse - and a third under construction, the Msh2G674S mutant mouse. Each of these will be compared to wild-type mice. Each model will be maintained on control AIN76A diet as well as a new western style high risk diet (nwdiet#1) that is sufficient to induce premalignant changes and tumor formation in wild-type mice - a diet high in fat and phosphate, low in calcium, vitamin D, choline, methionine and folate. Additional groups will consist of wild-type mice and each of the genetic models maintained on the nwdiet#1 with calcium and vitamin D reconstituted back to control levels, and for the Apc1638 mice and wild type mice, groups in which each of the other constituents of the nwdiet#1 will be reconstituted individually. The primary endpoint is tumor formation, with detailed, standardized analysis also carried out by the Histopathology Core to evaluate alterations in cell proliferation, apoptosis, lineage specific differentiation, and cell migration. The Genomics Core will perform microarray analysis utilizing RNA from each of four mice in each dietary/genetic group. Microarray analysis of the wild-type mice maintained on the control and nwdiet#1, as well as the nwdiet#1 with each component added back, has already been completed. The arrays are 27,000 member mouse cDNA arrays fabricated by the Albert Einstein Core Microarray facility, and the methodology for generation and analysis of the data has been well-established in our group. These data will be analyzed by the Genomics and the Biostatistics Cores in collaboration, and altered expression of important sequences confirmed through a combination of Real-Time PCR, laser capture microdissection and related methodologies in the Histopathology Core. The data will be fundamental in identifying genes and pathways that are modified by genetic and/or dietary factors in establishing relative risk for tumor formation, and the analysis will be instructed by microarray data bases we have already developed (published and unpublished) that dissect intestinal cell maturation pathways. These data will be highly interactive in interpreting similar data to be generated from biopsies of patients in Project 3. The data will also be integrated with data to be generated by the Genomics Core on genome wide alterations in methylation, to determine the extent to which altered gene expression is dependent upon altered locus methylation, and to identify subsets of genes regulated in this manner. Sequences identified in this Project will be prioritized for application of unique technological resources in the Genomics Core for functional studies, utilizing methods of Imaging of Transcription Sites in situ, and high-throughput Structural Proteomics. Finally, the tissue from the mice in this Project will be banked by the Histopathology Core. The tissues will be distributed to Project 2 for studies on the role of the ?-catenin-Tcf -- c-myc/cyclin D1/cdk4 -- p21/p27 pathway, and its intersections with machinery of the cell cycle, and investigation of a novel method of regulation of c-myc transcription by nutritional factors. The tissue is also used by the Histopathology Core for the generation of Tissue Arrays.